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BioRxiv : the Preprint Server For... Feb 2024Prairie voles () and Syrian, or golden, hamsters () are closely related to mice () and rats (, for example) and are commonly used in studies of social behavior including...
Prairie voles () and Syrian, or golden, hamsters () are closely related to mice () and rats (, for example) and are commonly used in studies of social behavior including social interaction, social memory, and aggression. The CA2 region of the hippocampus is known to play a key role in social memory and aggression in mice and responds to social stimuli in rats, likely owing to its high expression of oxytocin and vasopressin 1b receptors. However, CA2 has yet to be identified and characterized in hamsters or voles. In this study, we sought to determine whether CA2 could be identified molecularly in vole and hamster. To do this, we used immunofluorescence with primary antibodies raised against known molecular markers of CA2 in mice and rats to stain hippocampal sections from voles and hamsters in parallel with those from mice. Here, we report that, like in mouse and rat, staining for many CA2 proteins in vole and hamster hippocampus reveals a population of neurons that express regulator of G protein signaling 14 (RGS14), Purkinje cell protein 4 (PCP4) and striatal-enriched protein tyrosine phosphatase (STEP), which together delineate the borders with CA3 and CA1. These cells were located at the distal end of the mossy fiber projections, marked by the presence of Zinc Transporter 3 (ZnT-3) and calbindin in all three species. In addition to staining the mossy fibers, calbindin also labeled a layer of CA1 pyramidal cells in mouse and hamster but not in vole. However, Wolframin ER transmembrane glycoprotein (WFS1) immunofluorescence, which marks all CA1 neurons, was present in all three species and abutted the distal end of CA2, marked by RGS14 immunofluorescence. Staining for two stress hormone receptors-the glucocorticoid (GR) and mineralocorticoid (MR) receptors-was also similar in all three species, with GR staining found primarily in CA1 and MR staining enriched in CA2. Interestingly, although perineuronal nets (PNNs) are known to surround CA2 cells in mouse and rat, we found that staining for PNNs differed across species in that both CA2 and CA3 showed staining in voles and primarily CA3 in hamsters with only some neurons in proximal CA2 showing staining. These results demonstrate that, like in mouse, CA2 in voles and hamsters can be molecularly distinguished from neighboring CA1 and CA3 areas, but PNN staining is less useful for identifying CA2 in the latter two species. These findings reveal commonalities across species in molecular profile of CA2, which will facilitate future studies of CA2 in these species. Yet to be determined is how differences in PNNs might relate to differences in social behavior across species.
PubMed: 38405991
DOI: 10.1101/2024.02.12.579957 -
ACS Omega Jan 2024Cadmium, a ubiquitous environmental pollutant, has been implicated in the disruption of various metabolic pathways, contributing to the development of insulin...
Cadmium, a ubiquitous environmental pollutant, has been implicated in the disruption of various metabolic pathways, contributing to the development of insulin resistance, glucose intolerance, and associated metabolic disorders. This study aimed to investigate the cadmium chloride (CdCl) exposure on metabolic pathways and to assess the potential therapeutic efficacy of the taxifolin-enriched extract in mitigating these disruptions by modulating biochemical pathways. Taxifolin-enriched extract (TEE) was prepared from bark using a green extraction method. About 60 Wistar albino rats were divided into six groups: the control group ( = 10), the CdCl group (30 mg/kg) ( = 10), and four groups (each comprises = 10) treated with 30 mg/kg CdCl in combination with metformin (100 mg/kg), ascorbic acid, taxifolin (30 mg/kg), and TEE (30 mg/kg), respectively. After the treatment period of 1 month, a comprehensive assessment of metabolic biomarkers and gene expressions that regulate the metabolism of carbohydrates and lipids was conducted to evaluate the impact of CdCl exposure and the potential protective effects of TEE. The results revealed that CdCl exposure significantly increased ( < 0.001) serum levels of α-glucosidase, α-amylase, insulin, G6PC, hexokinases, TGs, LDL, HMG-CoA reductase, and pro-inflammatory cytokines such as IL-6 and TNF-α. Conversely, CdCl exposure led to a reduction in HDL, antioxidant enzyme levels, phosphofructokinases, and glucose-6-phosphatase dehydrogenase. However, the administration of TEE alongside CdCl substantially mitigated ( < 0.001) these fluctuations in metabolic and inflammatory biomarker levels induced by CdCl exposure. Both TEE and taxifolin treatment effectively lowered the elevated levels of α-amylase, α-glucosidase, G6PC, insulin, TGs, HMG-CoA reductase, leptin, ALT, AST, blood urea nitrogen, creatinine, and pro-inflammatory cytokines while simultaneously enhancing levels of HDL cholesterol and antioxidant enzymes. Moreover, CdCl exposure suppressed mRNA expression of critical metabolic biomarkers such as glucose transporter 2 (GLUT2), insulin-like growth factor 1 (IGF-1), lactate dehydrogenase, and HMG-CoA lyases while upregulating the mRNA expression of angiotensin receptor 2 and vasopressin, key metabolic biomarkers involved in glucose metabolism and insulin regulation. TEE demonstrated the potential to restore normal metabolic functions and reduce the adverse impacts caused by CdCl exposure by mitigating disturbances in several metabolic pathways and restoring gene expression of critical metabolic biomarkers related to glucose metabolism and insulin regulation. Nevertheless, further investigation is warranted to comprehensively understand the underlying mechanisms and optimize the appropriate dosage and duration of TEE treatment for achieving the most effective therapeutic outcomes.
PubMed: 38284084
DOI: 10.1021/acsomega.3c08989 -
Kidney International Reports Aug 2023Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic cause of kidney failure. Tolvaptan, a vasopressin 2 receptor antagonist, is the first...
INTRODUCTION
Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic cause of kidney failure. Tolvaptan, a vasopressin 2 receptor antagonist, is the first drug with proven disease-modifying activity. Long-term treatment adherence is crucial, but a considerable fraction of patients discontinue treatment, because of aquaretic side effects.
METHODS
Twenty-four-hour urine was collected in 75 patients with ADPKD during up-titration of tolvaptan and, in combination with clinical characteristics, examined to identify factors influencing urine volume. Patient-reported outcomes were analyzed using the Short Form-12 (SF-12) and patient-reported outcomes questionnaires reporting micturition frequency and burden of urine volume.
RESULTS
Initiation of therapy led to a large increase in urine volume followed by only minor further increase during up-dosing. Younger patients and patients with better kidney function experienced a larger relative rise. Twenty-four-hour urine osmolality dropped by about 50% after therapy initiation independently of dose, with a considerable proportion of patients achieving adequate suppression. Sodium and potassium intake turned out to be the only significant modifiable factors for urine volume after multivariate linear regression models, whereas age and weight could be identified as non-modifiable factors. No change in quality of life (QoL) was detected in relation to treatment or urine volume using SF-12 questionnaires, a finding that was further supported by the results of the patient-reported outcomes assessment.
CONCLUSION
This study provides an in-detail analysis of factors associated with the degree of polyuria on tolvaptan and puts them into the context of QoL. These findings will contribute to optimized patient counseling regarding this treatment option in ADPKD.
PubMed: 37547529
DOI: 10.1016/j.ekir.2023.05.011 -
Current Issues in Molecular Biology Oct 2023Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that affects social interactions, communication, and behavior. Although the predominant genetic...
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that affects social interactions, communication, and behavior. Although the predominant genetic predisposition to ASD seems beyond doubt, its exact nature remains unclear. In the context of social cognition disorders and the basis of ASD, the oxytocinergic and vasopresynergic systems arouse great interest among researchers. The aim of the present study was to analyze gene expression levels for oxytocin and vasopressin receptors, as well as CD38 protein and oxytocinase, in the context of the clinical picture of autism spectrum disorders. The study included 90 people, of whom 63 were diagnosed with ASD based on anamnesis, mental status testing, and the ADOS-2 protocol. The results obtained in the presented study indicate that the balance between the levels of expression of the CD38 gene and the oxytocinase gene plays a key role in the risk and clinical presentation of ASD. In a hypothetical scenario, an imbalance in the expression of CD38 and LNPEP could potentially lead to alterations in the concentrations of oxytocin and vasopressin. At the same time, the most frequently studied genes-AVPR1a and OXTR-seem to be at best of marginal importance for the risk of ASD.
PubMed: 37886970
DOI: 10.3390/cimb45100527 -
International Journal of Molecular... Sep 2023Vasopressin/oxytocin (VP/OT)-type neuropeptide is an ancient neurophysin-associated neuropeptide and has been intensively studied to be involved in multiple...
Vasopressin/oxytocin (VP/OT)-type neuropeptide is an ancient neurophysin-associated neuropeptide and has been intensively studied to be involved in multiple physiological processes in protostomian and deuterostome vertebrates. However, little is known about the functions of VP/OT-type neuropeptide in deuterostome invertebrates especially in echinoderms. Here, we firstly report VP/OT-type neuropeptide signaling in an important economic species, , which is widely cultured in Asia, with high nutritional and medicinal values. Molecular characterization analysis of holotocin and its precursor revealed the highly conserved features of VP/OT family. The candidate receptor for holotocin (AjHOR) was confirmed to be able to activate the signaling via cAMP-PKA and possible Ca-PKC pathway, and further activated the downstream ERK1/2 cascade. Holotocin precursor expression profile showed that they were mainly concentrated in circumoral nerve ring. Furthermore, in vitro pharmacological experiments demonstrated that holotocin caused contractile responses in preparations from . And in vivo functional studies indicated that short-term injection of holotocin resulted in body bloat and long-term injection resulted in reduced body mass, suggesting potential roles of holotocin in osmoregulation and feeding co-inhibition with holotocin-CCK. Our findings provided a comprehensive description of AjHOR-holotocin signaling, revealed ancient roles of holotocin in osmoregulation and feeding inhibition by controlling muscle contractions.
PubMed: 37762661
DOI: 10.3390/ijms241814358 -
Frontiers in Cellular Neuroscience 2023Social behavioral changes are a hallmark of several neurodevelopmental and neuropsychiatric conditions, nevertheless the underlying neural substrates of such dysfunction...
Selective oxytocin receptor activation prevents prefrontal circuit dysfunction and social behavioral alterations in response to chronic prefrontal cortex activation in male rats.
INTRODUCTION
Social behavioral changes are a hallmark of several neurodevelopmental and neuropsychiatric conditions, nevertheless the underlying neural substrates of such dysfunction remain poorly understood. Building evidence points to the prefrontal cortex (PFC) as one of the key brain regions that orchestrates social behavior. We used this concept with the aim to develop a translational rat model of social-circuit dysfunction, the chronic PFC activation model (CPA).
METHODS
Chemogenetic designer receptor hM3Dq was used to induce chronic activation of the PFC over 10 days, and the behavioral and electrophysiological signatures of prolonged PFC hyperactivity were evaluated. To test the sensitivity of this model to pharmacological interventions on longer timescales, and validate its translational potential, the rats were treated with our novel highly selective oxytocin receptor (OXTR) agonist RO6958375, which is not activating the related vasopressin V1a receptor.
RESULTS
CPA rats showed reduced sociability in the three-chamber sociability test, and a concomitant decrease in neuronal excitability and synaptic transmission within the PFC as measured by electrophysiological recordings in acute slice preparation. Sub-chronic treatment with a low dose of the novel OXTR agonist following CPA interferes with the emergence of PFC circuit dysfunction, abnormal social behavior and specific transcriptomic changes.
DISCUSSION
These results demonstrate that sustained PFC hyperactivity modifies circuit characteristics and social behaviors in ways that can be modulated by selective OXTR activation and that this model may be used to understand the circuit recruitment of prosocial therapies in drug discovery.
PubMed: 38145283
DOI: 10.3389/fncel.2023.1286552 -
Frontiers in Veterinary Science 2023Follicular cysts are a common reproductive disorder in mammals that is usually caused by stress. However, the pathogenesis of follicular cysts in sows remains unclear....
Follicular cysts are a common reproductive disorder in mammals that is usually caused by stress. However, the pathogenesis of follicular cysts in sows remains unclear. To provide new insights into the mechanisms of follicular cyst formation in pigs, we conducted a combined transcriptomic and metabolomic analysis on theca interna and mural granulosa cells of follicular cysts and mature follicles. We identified 2,533 up-regulated and 1,355 down-regulated genes in follicular cysts, compared with mature follicles. These differentially expressed genes were mainly found in signaling pathways related to tumor formation and cortisol synthesis and secretion as shown by Ingenuity Pathway Analysis, which predicted 4,362 upstream regulatory factors. The combined gene expression and pathway analysis identified the following genes as potential biomarkers for porcine follicular cysts: . Metabolomics analysis found significant differences in 87 metabolites, which were enriched in unsaturated fatty acid biosynthesis, and sphingolipid signaling pathways. These results provide valuable information on the molecular mechanisms of follicular cyst formation, which may facilitate the development of new therapeutics to prevent and treat follicular cysts.
PubMed: 38274662
DOI: 10.3389/fvets.2023.1298132 -
PloS One 2023This study aimed to evaluate whether exercise training could contribute to a better modulation of the neurohumoral mechanisms linked to the pathophysiology of arterial...
Concurrent exercise training induces additional benefits to hydrochlorothiazide: Evidence for an improvement of autonomic control and oxidative stress in a model of hypertension and postmenopause.
OBJECTIVE
This study aimed to evaluate whether exercise training could contribute to a better modulation of the neurohumoral mechanisms linked to the pathophysiology of arterial hypertension (AH) in postmenopausal hypertensive rats treated with hydrochlorothiazide (HCTZ).
METHODS
Female spontaneously hypertensive rats (SHR) (150-200g, 90 days old) were distributed into 5 hypertensive groups (n = 7-8 rats/group): control (C), ovariectomized (O), ovariectomized treated with HCTZ (OH), ovariectomized submitted to exercise training (OT) and ovariectomized submitted to exercise training and treated with HCTZ (OTH). Ovarian hormone deprivation was performed through bilateral ovariectomy. HCTZ (30mg/kg/day) and concurrent exercise training (3d/wk) were conducted lasted 8 weeks. Arterial pressure (AP) was directly recorded. Cardiac effort was evaluated using the rate-pressure product (RPP = systolic AP x heart rate). Vasopressin V1 receptor antagonist, losartan and hexamethonium were sequentially injected to evaluate the vasopressor systems. Inflammation and oxidative stress were evaluated in cardiac tissue.
RESULTS
In addition to the reduction in AP, trained groups improved RPP, AP variability, bradycardic (OT: -1.3 ± 0.4 and OTH: -1.6 ± 0.3 vs. O: -0.6 ± 0.3 bpm/mmHg) and tachycardic responses of baroreflex sensitivity (OT: -2.4 ± 0.8 and OTH: -2.4 ± 0.8 vs. O: -1.3 ± 0.5 bpm/mmHg), NADPH oxidase and IL-10/TNF-α ratio. Hexamethonium injection revealed reduced sympathetic contribution on basal AP in OTH group (OTH: -49.8 ± 12.4 vs. O: -74.6 ± 18.1 mmHg). Furthermore, cardiac sympathovagal balance (LF/HF ratio), IL-10 and antioxidant enzymes were enhanced in OTH group. AP variability and baroreflex sensitivity were correlated with systolic AP, RPP, LF/HF ratio and inflammatory and oxidative stress parameters.
CONCLUSION
The combination of HCTZ plus concurrent exercise training induced additional positive adaptations in cardiovascular autonomic control, inflammation and redox balance in ovariectomized SHR. Therefore, combining exercise and medication may represent a promising strategy for managing classic and remaining cardiovascular risks in AH.
Topics: Rats; Female; Animals; Postmenopause; Interleukin-10; Hydrochlorothiazide; Hexamethonium; Rats, Wistar; Hypertension; Blood Pressure; Rats, Inbred SHR; Heart Rate; Oxidative Stress; Baroreflex; Inflammation
PubMed: 37549182
DOI: 10.1371/journal.pone.0289715 -
Journal of Pharmacokinetics and... Jun 2024Balovaptan is a brain-penetrating vasopressin receptor 1a antagonist previously investigated for the core symptoms of autism spectrum disorder (ASD). A population...
Balovaptan is a brain-penetrating vasopressin receptor 1a antagonist previously investigated for the core symptoms of autism spectrum disorder (ASD). A population pharmacokinetic (PK) model of balovaptan was developed, initially to assist clinical dosing for adult and pediatric ASD studies and subsequently for new clinical indications including malignant cerebral edema (MCE) and post-traumatic stress disorder. The final model incorporates one-compartment disposition and describes time- and dose-dependent non-linear PK through empirical drug binding and a gut extraction component with turnover. An age effect on clearance observed in children was modeled by an asymptotic function that predicts adult-equivalent exposures at 40% of the adult dose for children aged 2-4 years, 70% for 5-9 years, and at the full adult dose for ≥ 10 years. The model was adapted for intravenous (IV) balovaptan dosing and combined with in vitro and ex vivo pharmacodynamic data to simulate brain receptor occupancy as a guide for dosing in a phase II trial of MCE prophylaxis after acute ischemic stroke. A sequence of three stepped-dose daily infusions of 50, 25 and 15 mg over 30 or 60 min was predicted to achieve a target occupancy of ≥ 80% in ≥ 95% of patients over a 3-day period. This model predicts both oral and IV balovaptan exposure across a wide age range and will be a valuable tool to analyze and predict its PK in new indications and target populations, including pediatric patients.
Topics: Humans; Child; Child, Preschool; Models, Biological; Adult; Dose-Response Relationship, Drug; Antidiuretic Hormone Receptor Antagonists; Adolescent; Male; Female; Benzazepines; Young Adult; Brain Edema; Middle Aged; Brain
PubMed: 38308741
DOI: 10.1007/s10928-023-09898-0 -
Journal of Experimental Pharmacology 2023Management of decompensated cirrhosis may include the use of vasoconstrictors that can lead to serious adverse events. OCE-205 was designed as a highly selective V1a...
PURPOSE
Management of decompensated cirrhosis may include the use of vasoconstrictors that can lead to serious adverse events. OCE-205 was designed as a highly selective V1a receptor partial agonist, intended to have a wider therapeutic window than full vasopressin agonists.
METHODS
We aimed to characterize the activity of OCE-205 treatment in two rat models of portal hypertension (PHT). For both models, OCE-205 was administered as a subcutaneous bolus injection. Thirty male Wistar rats were fed a methionine/choline-deficient (MCD) diet to model PHT. Animals received OCE-205 (10, 25, 100, or 500 µg/kg) or intra-arterial terlipressin (100 µg/kg). In a more severe model of PHT, 11 male Sprague Dawley rats had the common bile duct surgically ligated (BDL) and received OCE-205. Portal pressure (PP) and mean arterial pressure (MAP) were measured.
RESULTS
For PP in the MCD model, MAP increased while PP decreased in rats treated with OCE-205 or terlipressin; the peak changes to MAP were 14.7 and 33.5 mmHg, respectively. Changes in MAP began to plateau after 10 min in the OCE-205 groups, whereas in the terlipressin group, MAP rapidly increased and peaked after 20 min. Across all treatment groups in the BDL model, a dose-related decrease from baseline in PP was observed following OCE-205, plateauing as the dose increased. In all treatment groups, PP change remained negative throughout the 30-min testing period. In both PHT rat models, a reduction in PP was coupled to an increase in MAP, with both plateauing in dose-response curves.
CONCLUSION
Data support OCE-205 as a promising candidate for further development.
INSTITUTIONAL PROTOCOL NUMBER
Procedures were approved by the Ferring Research Institute (FRI) Institutional Animal Care and Use Committee on July 13, 2011, under protocol FRI-07-0002.
PubMed: 37469992
DOI: 10.2147/JEP.S416673